1-methoxyhexane

Endpoint summary

Description of key information

Acute oral toxicity: 720 mg/kg bw (720 and 1800 mg/kg bw for females and males, respectively), based on read-across from 1 -Hexanol, which was tested in OECD TG 401.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Remarks:

1-Hexanol

Adequacy of study:

key study

Study period:

The study was conducted in 1968.

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

Four rats were used instead of five; their weight was lower than recommended in the guideline; rats were starved for 24 instead of 12 h; it is not reported how many doses were used; rats were killed after 10 instead of 14 days.

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

Rats weighed between 60 and 100 g.
The animals were starved for 24 h prior to dosing.

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Details on oral exposure:

Diola was administered by gavage. Doses of less than 0.1 ml were made up to 0.25 ml with the vehicle.

Doses:

The range of doses used in this study was selected after a preliminary experiment had established the approximate degree of toxicity. The log interval between doses was constant, allowing the LD50 values to be calculated. The dose ranges used were 440-8800 mg/kg in males and 90-4400 mg/kg in females.

No. of animals per sex per dose:

4 rats per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 10 days
- Necropsy of survivors performed: yes, at death or at the end of the observation period. Portions of heart, liver, lung and kidney from representative rats in each group were fixed in buffered formalin and embedded in wax. Sections were stained with haematoxylin and erythrosin.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

720 mg/kg bw

Based on:

test mat.

Remarks on result:

other: This value will be taken forward to the risk assessment

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

1 800 mL/kg bw

Based on:

test mat.

Mortality:

Most rats receiving a lethal dose died within 24, only two surviving to 4 to 5 days.

Clinical signs:

No observations

Body weight:

No information provided.

Gross pathology:

Histological examination of the liver sections showed hyperaemia in the animals dying within 24 hrs, and in a few rats a slight fatty infiltration. The sections from other rats were essentially normal. There was no difference between the males and females in this respect. In the kidney at the lowest dose, hyperaemia and cloudy swellings were present in the cortex and hyperaemia in the medulla. At the next dose, pyknosis was present in the tubular cells of the medulla of the kidney. These changes were more advanced in the kidney at higher doses, with marked medullary necrosis and hyperaemia and cloudy swelling, cast formation and hyperaemia in the cortex in the highest dose range.

Other findings:

No other findings were noted.

Interpretation of results:

other: Acute Oral Category 4

Remarks:

According to EU CLP 1272/2008 and its amendments.

Conclusions:

The acute oral LD50 for the substance in male and female rats was 1800 and 720 mg/kg bw. The value of 720 mg/kg bw is taken forward in the risk assessment being the more conserative value.

Executive summary:

Acute oral toxicity with the 1-Hexanol was performed similar to the guideline OECD TG 401. Four rats (females and males) were used per dose. They were administered the substance at dose levels of 440 -8800 mg/kg in males and 90-4400 mg/kg in females. These doses were selected based on a preliminary study. Mortality occurred most in the first day after dosing. In the liver hyperaemia (increased blood flow) was found. Hyperaemia was also seen in the kidneys in the cortex and more pronounced in the medulla. At the mid and high dose also pyknosis was seen in the tubular cells of the medulla, indicating cell death. The acute oral LD50 for 1-Hexanol in males was 1800 and in females 720 mg/kg bw. The LD50 is set as 720 mg/kg bw being the most conservative value.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Read across information

Justification for type of information:

The full read-across document can be found in the Endpoint Summary in text and in the attached file.

Reason / purpose for cross-reference:

read-across source

GLP compliance:

no

Test type:

other: Read across information

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

720 - 1 800 mg/kg bw

Based on:

test mat.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

720 mg/kg bw

Additional information

The acute oral toxicity is based on read across from 1-Hexanol. First the acute oral toxicity information on 1-Hexanol is presented and thereafter the read across justification is presented.

Acute oral toxicity with 1-Hexanol:

Acute oral toxicity with the 1-Hexanol was performed similar to the guideline OECD TG 401. Four rats (females and males) were used per dose. They were administered the substance at dose levels of 440 -8800 mg/kg in males and 90-4400 mg/kg in females. These doses were selected based on a preliminary study. Mortality occurred most in the first day after dosing. In the liver hyperaemia (increased blood flow) was found. Hyperaemia was also seen in the kidneys in the cortex and more pronounced in the medulla. At the mid and high dose also pyknosis was seen in the tubular cells of the medulla, indicating cell death. The acute oral LD50 for 1-Hexanol in males was 1800 and in females 720 mg/kg bw. The LD50 is set as 720 mg/kg bw being the most conservative value.

The acute oral toxicity of Diola using read across from 1-Hexanol (CAS#111-27-3)

Introduction and hypothesis for the analogue approach

Diola is an alkane structure of six carbons with an ether functional group on one end. For this substance no acute oral toxicity data are available. In accordance with Article 13 of REACH, lacking information should be generated whenever possible by means other than vertebrate animal tests, i.e. applying alternative methods such as in vitro tests, QSARs, grouping and read-across. For assessing the acute oral toxicity of Diola, the analogue approach is selected because for one, closely related, analogue acute oral toxicity information is available which can be used for read across.

Hypothesis: Diola has similar acute oral toxicity compared to the 1-Hexanol resulting in a similar LD50 because Diola will metabolize into Hexanol and therefore the systemic exposure will be to Hexanol.

Available information: There are no data for the target substance, Diola. The source chemical, 1-Hexanol, has been tested in a well conducted acute oral toxicity test (OECD TG 401) up to 8800 mg/kg bw.The LD50 was 720 and 1800 mg/kg bw for females and males, respectively. The lowest LD50 is used: 720 mg/kg bw. The study receives a reliability code 2. Though more acute oral toxicity information is available on Hexanol, the current study is selected because the study presents the lowest LD50 and is reliable.

Target chemical and source chemical(s)

The target is Diola and the source is 1-Hexanol. Chemical structures of the target chemical and the source chemical are shownin the data matrixbelow, including physico-chemical properties and toxicological information, thought to be relevant for acute oral toxicity.

Purity / Impurities

Diola is a mono-constituent. The impurities of the target chemical do not indicate acute oral toxicity potential other than indicated by the parent substance. The impurities are all below < 10%.

Analogue approach justification

According to Annex XI 1.5, read across can be used to replace testing when the similarity can be based on a common backbone and a common functional group. When using read across, the result derived should be applicable for C&L and/or risk assessment and it should be presented with adequate and reliable documentation.

Analogue selection: In order to identify possible RA candidates, RIFM database and OECD QSAR toolbox were used for searchof analogues. From all identified analogues, 1-Hexanol is the most similar to Diola based on structure and the non-reactive functional groups, alcohol and ether, respectively. This similarity is further supported with a Tanimoto similarity of 88%.

Structural similarities and difference: The target and the source chemicals have a very similar backbone, which is an alkane consisting of six carbons. Diola has an ether group with a methyl group attached while 1-Hexanol has solely an alcohol group.

Toxico-kinetic: Oral absorption: both substances will be fully absorbed: they have very similar molecular weights (116 and 102), both are liquids and they have similar physico-chemical properties. The one C extra in Diola presents a slightly higher log Kow and lower water solubility, which indicate similar high oral absorption. Metabolism: Diola will be metabolized into 1-Hexanol when it will be demethylated in the gut or liver.

 

Fig. 1 The metabolisation pathway of Diola and 1-Hexanol.

 

 

Toxico-dynamics: Upon oral exposure, the systemic toxicity of these two substances will be the same. The additional methyl group of Diola resulting in methanol will be easily converted during normal metabolic processes.

Uncertainty of the prediction: In view of the reasoning above there is no remaining uncertainty because the systemic toxicity will be to the same substance (1 -Hexanol). Conversion based on molecular weight was not performed because the LD50 of 1-Hexanol is conservative in view of its lower molecular weight compared to Diola.

Conclusions per endpoint for hazard and C&L

When using read across the result derived should be applicable for C&L and/or risk assessment, cover an exposure period duration comparable or longer than the corresponding method and be presented with adequate and reliable documentation. For 1-Hexanol a well conducted acute oral toxicity test is available (Reliability 2) with an LD50 of720 mg/kg in rats. Based on the read across, the same LD50 for Diola is derived. The Hexanol value is conservative, due to higher molecular weight of Diola and therefore conversion has not been done.

Final conclusion on hazard and C&L: Based on 1-Hexanol information, Diola is anticipated to have an LD50 of 720 mg/kg in rats and is classified accordingly.

Data matrix for the read across of Diola from 1-Hexanol

Common names	Diola	1-Hexanol
Chemical structures
CAS no	4747-07-3	111-27-3
REACH registration	Registered for 2018	Registered
EC number	225-263-0	203-852-3
Empirical formula	C7H16O	C6H14O
Molecular weight	116.21	102.18
Physico-chemical data
Physical state	Clear liquid (IFF, 2016)	Colorless liquid
Melting point,^oC	-62.71 (C) <20 (IFF, 2016)	-37.86 (C)
Boiling point,^oC	120.78 (C) 134.1 (IFF, 2016)	159.09 (C)
Vapour pressure, Pa	1930 (C) 2185 (IFF, 2016)	117 (C)
Water solubility, mg/l	726.2 (C) 660.9 (IFF, 2016)	6885 (C)
Log Kow	2.52 (C) 3.6 (IFF, 2016)	1.82 (C) 1.80 (M)
Human health endpoints
Toxico-kinetics: Metabolisation	Demethylation into 1-Hexanol
Acute oral tox in mg/kg bw	Read across from 1-Hexanol	LD50 = 720 (OECD TG 401)
Genotoxicity – Ames test	Negative	Negative

 

Justification for classification or non-classification

The substance has to be classified as Acute Oral Category 4 based on read across from Hexanol by the oral route in accordance with EU CLP regulation (1272/2008) and its amendments.